Focal and segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, it is clear that the glomerular podocyte plays a central role in disease pathogenesis. In the current proposal, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is dramatically upregulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples. We show that sdk-1 strongly interacts with the slit diaphragm linker protein MAGI-1, which is already known to interact with several critical podocyte proteins including synaptopodin, a-actinin-4, nephrin, JAM4, and -catenin. Furthermore, transgenic mice with podocyte-specific overexpression of sdk-1 develop gradual proteinuria, nephrosis, and FSGS. Similarly, MAGI-1 deficient mice also develop gradually progressive proteinuria and FSGS. The similarities between the phenotypes of these two novel mouse models and the fact that the two involved proteins directly interact suggest that similar pathogenic factors may be involved in both models. We hypothesize that the overexpression of sdk-1 in podocytes in FSGS disrupts the ability of MAGI-1 to stabilize podocyte architecture and that over time this leads to the development of glomerular sclerosis. To confirm and identify the involved mechanisms, we propose three specific aims: 1) To determine how the overexpression of sdk-1 affects the binding of MAGI-1 to other critical podocyte proteins. 2) To characterize the renal phenotype of MAGI-1 null mice and to compare it to the phenotype of the podocyte-specific sdk-1 overexpression model. 3) To test the susceptibility of sdk-1 knockout mice to podocyte injury and to the development of FSGS. In this way, we will demonstrate that sdk-1 upregulation is an important factor contributing to the pathogenesis of FSGS and could represent a novel therapeutic target. PUBLIC HEALTH RELEVANCE: Focal and segmental glomerulosclerosis is the leading cause of idiopathic nephrotic syndrome in the United States and the most common cause of end stage renal disease caused by primary glomerular disease worldwide. In this project, we identify a novel mechanism that contributes greatly to the pathogenesis of this important disease and may lead to the identification of novel potential therapeutic targets.